Bipolar disorder (BD) is characterized by recurring episodes of alternating mania and depression, has a complex pathophysiology and a polygenic risk, in addition to reduction in neural volumes and alterations in neurotransmission (Consortium 2009; Boies et al., 2017). Chen et al. (2014) examined changes in gene expression throughout the course of directed differentiation from hiPSCs to mixed-population neurons derived from three patients and three age-matched controls. Overall no significant expression differences were observed in the pluripotent stage, but BD neurons expressed significantly more membrane receptors and ion channels, especially those involved in calcium signaling (Chen et al., 2014). Total RNAseq analyses of three-week-old hippocampal dentate gyrus granule cell-like neurons revealed enhancement in multiple mitochondrial genes in BD neurons. Flow cytometry and mitochondrial membrane potential measurements suggested an enhanced mitochondrial function. Patch-clamp recordings and calcium imaging at baseline and following exposure to lithium, a commonly used pharmacotherapy for BD, revealed lower threshold for action potentials and higher firing frequencies for BD neurons (Mertens et al., 2015b). Interestingly, BD neurons from lithium responders displayed a reduction in hyperexcitability following lithium treatment, in
